low-density lipoprotein

**Structure/Composition:** LDL is cholesterol ester–rich (the highest cholesterol content of the lipoproteins). Its sole apolipoprotein is ApoB-100, which binds the LDL receptor.

**Metabolism:** - The liver secretes VLDL (ApoB-100, ApoC-II, ApoE). Lipoprotein lipase (activated by ApoC-II) removes triglycerides, producing IDL. Hepatic lipase then converts IDL to LDL. - LDL delivers cholesterol to peripheral tissues and the liver. LDL receptors (recognizing ApoB-100 and ApoE) mediate receptor-mediated endocytosis via clathrin-coated pits. Lysosomal degradation then releases free cholesterol. - Intracellular free cholesterol inhibits HMG-CoA reductase, downregulates LDL receptor synthesis, and activates ACAT, which re-esterifies cholesterol for storage. - LCAT (activated by ApoA-I) esterifies cholesterol on HDL. CETP transfers cholesterol esters from HDL to VLDL/LDL. - PCSK9 promotes LDL receptor degradation, which raises LDL.

**Pathophysiology:** - Oxidized LDL is taken up by macrophages through scavenger receptors, producing foam cells. These form fatty streaks and then atherosclerotic plaques (the core of atherogenesis). - Small, dense LDL is more atherogenic. It is associated with metabolic syndrome, insulin resistance, and hypertriglyceridemia.

**Clinical associations:** - *Familial hypercholesterolemia (Type IIa):* autosomal dominant. Defects are in the LDL receptor (most common), ApoB-100 (familial defective ApoB-100), or gain-of-function PCSK9. Findings: severely elevated LDL, tendon (Achilles) xanthomas, corneal arcus, xanthelasma, and premature coronary artery disease. Heterozygotes have LDL ~300 mg/dL and homozygotes ~600+ mg/dL. - *Abetalipoproteinemia:* MTP deficiency leads to absent ApoB-containing lipoproteins (chylomicrons, VLDL, LDL). Findings: fat malabsorption, acanthocytes, steatorrhea, fat-soluble vitamin deficiencies (ataxia, retinitis pigmentosa), and failure to thrive. - *Secondary causes of high LDL:* hypothyroidism, nephrotic syndrome, cholestasis, and diet. - *Friedewald equation:* LDL = TC − HDL − (TG/5), valid only when TG <400 mg/dL.

**Targets/Treatment:** - Optimal LDL is <100 mg/dL. Goals are lower in very-high-risk patients, such as those with established ASCVD, and guidelines now often use LDL thresholds of 70 mg/dL or lower. - *Statins* (HMG-CoA reductase inhibitors) are first-line. They lower LDL the most, upregulate LDL receptors, and carry risks of myopathy/rhabdomyolysis and hepatotoxicity. - *Ezetimibe* blocks NPC1L1-mediated intestinal cholesterol absorption. - *PCSK9 inhibitors* (evolocumab, alirocumab) increase LDL receptor recycling. - *Bile acid resins* (cholestyramine) can raise TG and cause bloating. - *Bempedoic acid* inhibits ATP citrate lyase and can cause hyperuricemia and tendon rupture. - *Lomitapide* inhibits MTP and is used in homozygous familial hypercholesterolemia (HoFH), with a risk of hepatic steatosis. - *Niacin* modestly lowers LDL, but its use has declined.

**High-yield pearls:** LDL = "bad cholesterol" (ApoB-100). HDL = "good" (ApoA-I). ApoB-48 is on chylomicrons only. The LDL receptor binds ApoB-100 and ApoE. Statins are the first-line therapy with proven mortality benefit.